Insulin resistance (IR) is a condition in which cells and tissues have a decreased sensitivity to insulin, and secretion of insulin is increased to compensate for impaired glucose metabolism. The ability of insulin to stimulate glucose disposal has been reported to vary more than six-fold in apparently healthy individuals (Reaven et al. (2004) Recent Prog Horm Res 59:207-23), and it is well known that first-degree relatives of type 2 diabetics are often IR (Nyholm et al. (2004) Eur J Endocrinol 150:207-214). Individuals diagnosed as IR may show symptoms of IR syndrome also known as metabolic syndrome and syndrome X (Reaven GM (1988) Diabetes 37:1595-1607), and are at increased risk for developing non-insulin dependent Diabetes mellitus (NIDDM).
Two procedures that have been used to detect IR are euglycemic insulin clamp technique (EIC; Andres et al. In: Skeggs LT (1966) Automation in Analytical Chemistry. pp 486-491) and steady-state plasma glucose (SSPG) test (Greenfield MS (1982) Diabetes 30:387-392). Both methods monitor insulin-mediated glucose disposal in vivo and are considered to be the “gold-standard” for detection of IR. Both of these procedures are cumbersome in that they require hospitalization, multiple infusions using a catheter, and sampling over time. The limitations of EIC include the inability to reproduce physiological conditions, use of more than one dose of insulin to achieve a steady state glucose level, test complexity that precludes use in a clinical setting and, ultimately, cost.
Other methods for estimating IR include the minimal model (MM), an intravenous glucose tolerance test (Bergman et al. (1987) J Clin Invest 79:790-800), homeostasis model assessment (HOMA-IR; Matthews et al.(1985) Diabetologia 28:412-419) and quantitive insulin check index (QUICKI; Hrebicek et al. (2002) J Clin Endocrinol Metab 87:144-1470). HOMA-IR calculations are based on fasting glucose and insulin measurements [R=insulin (mU/L)/22.5e-In glucose(mmol/liter) or R=(insulin×glucose)/22.5) in simplified form]. QUICKI can be determined from fasting insulin and glucose values according to the equation. QUICKI=1/[log (I0)+log (G0)], in which I0 is fasting insulin and G0 is fasting glucose. There are also limitations for each of these methods, MM has variable accuracy in diabetics whose immediate plasma insulin response is already diminish, and HOMA-IR and QUICKI are indirect e s for IR that rely heavily on the fasting plasma glucose and insulin measurement which correlate poorly with EIC or SSPG data (Tuan C Y et al. (2003) Am J Cardiol 92:606-610).
Matsuda and DeFronzo (1999 D Care 22:1462-1477) Resented a method for evaluaating insulin sensitivity (IS) based on euglycemic insulin clamp studies. Although the authors developed a formula for calculating whole body IS correlated with oral glucose tolerance test (OGTT), the method was not reduced to or presented in a format easily adapted for clinical screening.
In a recent study, Facchini et al. (2001; J Clin Endocrin Metabol 86:3574-78) showed a strong correlation between the ability to use insulin in glucose metabolism and the onset of age-related diseases. Some 208 healthy, non-obese volunteers over 30 years of age were chosen for this SSPG study on the basis of body mass index less than 30, lack of hypertension, blood pressure less than 140/90 mm Hg, normal OGTT, physical examination and clinical chemistries Over a period of 4-11 years, volunteers were evaluated for development of age-related diseases. The most notable result from this study was that the most insulin sensitive volunteers had zero incidence of age-related diseases such as cancer, coronary heart disease, hypertension, NIDDM, and stroke. The authors stated a need for distinguishing subjects who were IS from those who were IR in order to monitor the development of age-related diseases in the IR group.
Because overweight individuals can be either IR or IS, McLaughlin et al. (2003, Annals of Internal Medicine 139:802-809) evaluated boy mass index; fasting glucose, SSPG, insulin, and lipid concentrations for the ability to identify the subset of overweight individuals who are IR. They reported that a triglyceride/high density lipoprotein cholesterol ratio (TG/HDL) is useful in identifying IR subjects.
IR and NIDDM have a strong genetic component (Abbasi et al. (2002) J Amer College Cardiol 40:937-43); so the ability to accurately identify susceptible individuals is of great importance. Adults with IR have up to 10 times greater risk of death from cardiovascular disease and are at greater risk for NIDDM—the leading cause of damage to or failure of eyes, kidneys and nerves According the World Health Organization, NIDDM is now the most costly healthcare issue worldwide.
Once there is an IR diagnosis, the subject can be counseled to modify diet, begin an exercise program, lose weight and take drugs to improve insulin sensitivity and delay onset of IR-related conditions and conversion to NIDDM (American Diabetes Association (ADA) 2002; Diabetes Care 25:742-49). The benefit of reducing healthcare costs associated with early diagnosis of IR, NIDDM and IR- or age-related diseases is well documented by the ADA (2003; Diabetes Care 26:917-32) and American Heart Association (AHA).
There is a need in the art for a more practical and cost-effective method for screening and diagnosing IS and IR. The earlier that subjects can be diagnosed as IS or IR, the greater the savings in terms of personal, medical and societal costs.